RESUMO

Ischemic heart disease refers to the imbalance between the supply and demand of myocardial blood; it has various causes and results in a class of clinical diseases characterized by myocardial ischemia (MI). In recent years, the incidence of cardiovascular disease has become higher and higher, and the number of patients with ischemic heart disease has also increased year by year. Traditional treatment methods include drug therapy and surgical treatment, both of which have limitations. The former maybe develop risks of drug resistance and has more significant side effects, while the latter may damage blood vessels and risk infection. At this stage, a new cell-free treatment method needs to be explored. Many research results have shown that exosomes from different cell sources can protect the ischemic myocardium via intercellular action methods, such as promoting angiogenesis, inhibiting myocardial fibrosis, apoptosis and pyroptosis, and providing a new basis for the treatment of MI. In this review, we briefly introduce the formation and consequences of myocardial ischemia and the biology of exosomes, and then focus on the role and mechanism of exosomes from different sources in MI. We also discuss the role and mechanism of exosomes pretreated with Chinese and Western medicines on myocardial ischemia. We also discuss the potential of exosomes as diagnostic markers and therapeutic drug for MI.

RESUMO

This retrospective study demonstrated that patients with advanced non-small cell lung cancer who experienced any-grade or grade 1-2 immune-related adverse events (irAEs) with immune checkpoint inhibitor plus chemotherapy (ICI+Chemo) as first-line treatment regimen had significantly longer progression-free survival (PFS; p < 0.001) and overall survival (OS; p < 0.05) compared with patients without any irAE. Three variables were identified as predictors of favorable PFS and OS: absence of baseline brain metastasis (p < 0.05), receiving first-line ICI+Chemo (p < 0.01), and occurrence of any grade adverse events (p < 0.001). Using these three variables, two nomograms were generated to predict PFS and OS, which were validated using two independent cohorts treated with Chemo or ICI+Chemo (n = 161) or ICI monotherapy (n = 109). Patients with low scores in discovery and validation cohorts consistently had significantly longer PFS (p < 0.001) and OS (p < 0.05) than those with high scores. Our findings provide preliminary evidence of the clinical utility of a nomogram in prognosticating ICI-treated patients.

RESUMO

DPP4 was considered a canonical receptor for merbecoviruses until the recent discovery of African bat-borne MERS-related coronaviruses using ACE2. The extent and diversity with which merbecoviruses engage ACE2 and their receptor species tropism remain unknown. Here, we reveal that HKU5 enters host cells utilizing Pipistrellus abramus (P.abr) and several non-bat mammalian ACE2s through a binding mode distinct from that of any other known ACE2-using coronaviruses. These results show that several merbecovirus clades independently evolved ACE2 utilization, which appears to be a broadly shared property among these pathogens, through an extraordinary diversity of ACE2 recognition modes. We show that MERS-CoV and HKU5 have markedly distinct antigenicity, due to extensive genetic divergence, and identified several HKU5 inhibitors, including two clinical compounds. Our findings profoundly alter our understanding of coronavirus evolution and pave the way for developing countermeasures against viruses poised for human emergence.

RESUMO

Excessive carbon dioxide ( CO 2 ) emissions pose a formidable challenge, driving global climate change and necessitating urgent attention. Striking a balance between curbing CO 2 emissions and fostering economic growth hinges upon the ability to reliably forecast CO 2 emissions. Such forecasts are indispensable for policymakers as they endeavor to make informed decisions and proactively implement mitigation measures. In this research, we introduce an innovative deep ensemble prediction model for CO 2 emissions. This model is constructed around four parallel Long Short-Term Memory (LSTM) neural networks, complemented by a novel Multi-Layer Perception (MLP)-based ensemble framework, equipped with an outlier detection mechanism and an order-invariant ranking module. To enhance prediction accuracy and stability, a k-nearest neighbor (KNN)-based outlier detection module is employed to identify non-outliers and reasonable predictions for the ensemble models. Additionally, a novel feature ranking module is proposed to mitigate prediction fluctuations. The performance evaluation of our model is conducted using historical CO 2 emission data spanning from 1971 to 2021, encompassing six representative countries. Our findings demonstrate that the proposed methodology outperforms existing approaches across various evaluation metrics, offering considerably reduced prediction variances and greater stability. Moreover, long-term CO 2 emission predictions for the corresponding six countries have been provided, which might offer policymakers some basis for making decisions.

RESUMO

The fascinating role of SPRR3 in various malignant tumors has prompted extensive research to unravel its expression patterns and prognostic significance. To comprehensively investigate SPRR3, we leveraged multiple datasets containing invaluable biomedical information, specifically focusing on the comparative analysis of SPRR3 gene expression levels across different cancer types. Meticulous examination of lung adenocarcinoma allowed us to delve deeper into the correlation between SPRR3 expression and its molecular biological functions. Our comprehensive analysis encompassed 33 malignant tumors, and the results unveiled significant differential expression of SPRR3 across a range of malignancies. Moreover, this aberrant expression of SPRR3 was observed to be closely associated with poorer prognosis in these malignant tumors. Notably, our investigation also unearthed a compelling link between SPRR3 and immune infiltrating cells in lung adenocarcinoma. The utilization of receiver operating characteristic (ROC) curves and survival curves in our study illustrated the immense potential of SPRR3 as a highly accurate predictor of cancer. These findings further emphasize the possibility of SPRR3 serving as a promising diagnostic and prognostic biomarker for a diverse array of cancers.

Assuntos

Adenocarcinoma de Pulmão , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Prognóstico , Biomarcadores Tumorais/genética , Curva ROC , Proteínas Ricas em Prolina do Estrato Córneo/genética , Proteínas Ricas em Prolina do Estrato Córneo/metabolismo

RESUMO

BACKGROUND: Limited data exists on the efficacy of immune checkpoint inhibitor (ICI) combinations in non-small-cell lung cancer (NSCLC) with uncommon driver alterations in genes such as ERBB2, BRAF, RET, and MET. This study retrospectively assessed ICI-combination therapy outcomes in this molecular subset of NSCLC. METHODS: We retrospectively analyzed patients with advanced NSCLC confirmed with driver alterations in genes including ERBB2, BRAF, RET or MET, and received ICI combined with chemotherapy (ICI + chemo) and/or targeted therapy (ICI + chemo/TT) as first-line (1L) or second- or third-line (≥ 2L) treatment at Hunan Cancer Hospital between January 2018 and May 2024. RESULTS: Of the 181 patients included in the study, 131 patients received 1L-ICI + chemo (ERBB2, n = 64; BRAF, n = 34; RET, n = 23; and MET, n = 10), and 50 patients received ≥ 2L-ICI + chemo/TT (ERBB2, n = 16; BRAF, n = 7; RET, n = 14; MET, n = 13). The full cohort had an overall response rate (ORR) of 45.9% and disease control rate of 84.0%. Among patients who received 1L-ICI + chemo, ORR ranged between 51.6% and 60.0%, with the median progression-free survival (mPFS) and overall survival (mOS) of 8.2 and 21.0 months for those with ERBB2-altered tumors, 10.0 and 15.0 months for BRAF-altered tumors, 12.1 months and OS not reached for RET-altered tumors, and 6.2 and 28.0 months for MET-altered tumors, respectively. Additionally, ORR ranged between 14.3% and 30.8% for ≥ 2L-ICI + chemo/TT; mPFS and mOS were 5.4 and 16.2 months for patients with ERBB2-altered tumors, 2.7 and 5.0 months for BRAF-altered tumors, 6.2 and 14.3 months for RET-altered tumors, and 5.7 and 11.5 months for MET-altered tumors, respectively. CONCLUSION: ICI-based combination therapies, regardless of treatment line, were effective in treating patients with advanced NSCLC harboring driver alterations in ERBB2, BRAF, RET, or MET. This suggests their potential as alternative treatment options in this patient population.

Assuntos

Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Receptor ErbB-2 , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-ret/genética , Resultado do Tratamento , Mutação , Proteínas Proto-Oncogênicas c-met/genética

RESUMO

Thirteen previously undescribed lindenane sesquiterpenoid dimers (LSDs), named chlorahololides G-S (1-13), were isolated from the whole plants of Chloranthus holostegius var. shimianensis, along with ten known analogues (14-23). The structures and absolute configurations of compounds 1-13 were elucidated through comprehensive spectroscopic analysis, NMR and electronic circular dichroism (ECD) calculations, and X-ray single-crystal diffraction. Chlorahololide G (1) represents the first instance of LSDs formed via a C-15-C-9' carbon-carbon single bond, whose plausible biosynthetic pathway was also proposed. Chlorahololides I and J (3 and 4) were deduced to be rare 8,9-seco and 9-deoxy LSDs with C-11-C-7' carbon-carbon bond, respectively. The inhibitory activity against NLRP3 inflammasome activation was evaluated for all isolates, with six compounds (5, 7, 8, 17, 22, and 23) exhibiting significant effects, and IC50 values ranging from 2.99 to 8.73 µM. Additionally, a preliminary structure-activity relationship analysis regarding their inhibition of NLRP3 inflammasome activation was summarized. Compound 17 exhibited dose-dependent inhibition of nigericin-induced pyroptosis in J774A.1 cells. Molecular docking studies suggested a strong interaction between compound 17 and NLRP3.

Assuntos

Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sesquiterpenos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Inflamassomos/metabolismo , Inflamassomos/antagonistas & inibidores , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/química , Animais , Camundongos , Simulação de Acoplamento Molecular , Dimerização , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação

RESUMO

BACKGROUND: In this study, we investigated the relationship between the risk of postoperative progressive disease (PD) in breast cancer and depression and sleep disorders in order to develop and validate a suitable risk prevention model. METHODS: A total of 750 postoperative patients with breast cancer were selected from the First People's Hospital of LianYunGang, and the indices of two groups (an event group and a non-event group) were compared to develop and validate a risk prediction model. The relationship between depression, sleep disorders, and PD events was investigated using the follow-up data of the 750 patients. RESULTS: SAS, SDS, and AIS scores differed in the group of patients who experienced postoperative disease progression versus those who did not; the differences were statistically significant and the ability to differentiate prognosis was high. The area under the receiver operating characteristic (ROC) curves (AUC) were: 0.8049 (0.7685-0.8613), 0.768 (0.727-0.809), and 0.7661 (0.724--0.808), with cut-off values of 43.5, 48.5, and 4.5, respectively. Significant variables were screened by single-factor analysis and multi-factor analysis to create model 1, by lasso regression and cross-lasso regression analysis to create model 2, by random forest calculation method to create model 3, by stepwise regression method (backward method) to create model 4, and by including all variables for Cox regression to include significant variables to create model 5. The AUC of model 2 was 0.883 (0.848-0.918) and 0.937 (0.893-0.981) in the training set and validation set, respectively. The clinical efficacy of the model was evaluated using decision curve analysis and clinical impact curve, and then the model 2 variables were transformed into scores, which were validated in two datasets, the training and validation sets, with AUCs of 0.884 (0.848-0.919) and 0.885 (0.818-0.951), respectively. CONCLUSION: We established and verified a model including SAS, SDS and AIS to predict the prognosis of breast cancer patients, and simplified it by scoring, making it convenient for clinical use, providing a theoretical basis for precise intervention in these patients. However, further research is needed to verify the generalization ability of our model.

Assuntos

Neoplasias da Mama , Depressão , Progressão da Doença , Nomogramas , Transtornos do Sono-Vigília , Humanos , Neoplasias da Mama/complicações , Feminino , Transtornos do Sono-Vigília/epidemiologia , Pessoa de Meia-Idade , Adulto , Depressão/epidemiologia , Idoso , Fatores de Risco , Curva ROC , Medição de Risco/métodos , Prognóstico

RESUMO

Background: The protective effectiveness provided by naturally acquired immunity against SARS-CoV-2 reinfection remain controversial. Objective: To systematically evaluate the protective effect of natural immunity against subsequent SARS-CoV-2 infection with different variants. Methods: We searched for related studies published in seven databases before March 5, 2023. Eligible studies included in the analysis reported the risk of subsequent infection for groups with or without a prior SARS-CoV-2 infection. The primary outcome was the overall pooled incidence rate ratio (IRR) of SARS-CoV-2 reinfection/infection between the two groups. We also focused on the protective effectiveness of natural immunity against reinfection/infection with different SARS-CoV-2 variants. We used a random-effects model to pool the data, and obtained the bias-adjusted results using the trim-and-fill method. Meta-regression and subgroup analyses were conducted to explore the sources of heterogeneity. Sensitivity analysis was performed by excluding included studies one by one to evaluate the stability of the results. Results: We identified 40 eligible articles including more than 20 million individuals without the history of SARS-CoV-2 vaccination. The bias-adjusted efficacy of naturally acquired antibodies against reinfection was estimated at 65% (pooled IRR = 0.35, 95% CI = 0.26-0.47), with higher efficacy against symptomatic COVID-19 cases (pooled IRR = 0.15, 95% CI = 0.08-0.26) than asymptomatic infection (pooled IRR = 0.40, 95% CI = 0.29-0.54). Meta-regression revealed that SARS-CoV-2 variant was a statistically significant effect modifier, which explaining 46.40% of the variation in IRRs. For different SARS-CoV-2 variant, the pooled IRRs for the Alpha (pooled IRR = 0.11, 95% CI = 0.06-0.19), Delta (pooled IRR = 0.19, 95% CI = 0.15-0.24) and Omicron (pooled IRR = 0.61, 95% CI = 0.42-0.87) variant were higher and higher. In other subgroup analyses, the pooled IRRs of SARS-CoV-2 infection were statistically various in different countries, publication year and the inclusion end time of population, with a significant difference (p = 0.02, p < 0.010 and p < 0.010), respectively. The risk of subsequent infection in the seropositive population appeared to increase slowly over time. Despite the heterogeneity in included studies, sensitivity analyses showed stable results. Conclusion: Previous SARS-CoV-2 infection provides protection against pre-omicron reinfection, but less against omicron. Ongoing viral mutation requires attention and prevention strategies, such as vaccine catch-up, in conjunction with multiple factors.

Assuntos

COVID-19 , Reinfecção , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , COVID-19/epidemiologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Imunidade Inata

RESUMO

The photocatalytic reduction of carbon dioxide (CO2) has emerged as a compelling strategy for the conversion of renewable energy. However, the expeditious recombination of photogenerated charge carriers and the inadequate light absorption capabilities are currently predominant challenges. Herein, we developed a facile hydrothermal approach to synthesize a sulfur doped Bi2O2CO3 nanosheet with a tunable energy band structure designed to enhance visible light absorption. Our findings indicate that the incorporation of sulfur into the catalytic sites induces an electron sink effect, significantly improving the separation efficiency of photogenerated charge carriers. Consequently, this sulfur-doped Bi2O2CO3 catalyst exhibits a remarkable carbon monoxide (CO) yield of 16.64 µmol gcat-1 h-1 with nearly 100 % selectivity under illumination ranging from 420 to 780 nm. Through in-situ characterization techniques and theoretical calculations, it was revealed that sulfur-coordinated bismuth sites greatly enhance CO2 adsorption and decrease the energy barrier for critical intermediates formation (*COOH), thus selectively driving the reaction towards CO production. This work not only advances our understanding of mechanisms underlying photocatalytic reduction of CO2 on sulfur-doped bismuth-based catalysts but also sets a precedent for developing sophisticated photocatalytic systems for enhanced photoreduction reactions.

RESUMO

This study aimed to evaluate the efficacy and safety of remimazolam for intraoperative sedation during regional anesthesia. It was a phase II-multicenter, randomized, single-blind, parallel-group, active-controlled clinical trial (No. ChiCTR2100054956). From May 6, 2021 to July 4, 2021, patients were randomly enrolled from 17 hospitals in China. A total of 105 patients aged 18-65 years who underwent selective surgery under regional anesthesia were included. Patients received different sedatives with different dosages: 0.1 mg/kg remimazolam (HR), 0.05 mg/kg remimazolam (LR), or 1.0 mg/kg propofol (P) group, followed by a maintenance infusion. Main outcome measures included the efficacy of sedation measured by Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) levels (1-4, 1-3, 2-3, 3, and 2-4) during the sedation procedure (the duration percentage) and incidence of adverse reactions. It showed that the duration percentage of MOAA/S levels 1-4 was 100.0 [8.1]% (median [interquartile range]), 89.9 [20.2]%, 100.0 [7.7]% in the HR, LR, and P groups, respectively. The percentage of patients in the HR, LR, and P groups who achieved MOAA/S levels 1-4 within 3 min after administration was 85.7%, 58.8%, and 82.9%, respectively. However, the time to recovery from anesthesia after withdrawal of sedatives (7.9 ± 5.7 min), incidence of anterograde amnesia (75%), and adverse effects were not statistically significant among the three groups. These findings suggest that a loading dose of remimazolam 0.1 mg/kg followed by a maintenance infusion of 0-3 mg/kg/h provides adequate sedation for patients under regional anesthesia without increasing adverse reactions.

RESUMO

SARS-CoV-2 infection is initiated by Spike glycoprotein binding to the human angiotensin-converting enzyme 2 (ACE2) receptor via its receptor binding domain. Blocking this interaction has been proven to be an effective approach to inhibit virus infection. Here we report the discovery of a neutralizing nanobody named VHH60, which was directly produced from an engineering nanobody library based on a commercialized nanobody within a very short period. VHH60 competes with human ACE2 to bind the receptor binding domain of the Spike protein at S351, S470-471and S493-494 as determined by structural analysis, with an affinity of 2.56 nM. It inhibits infections of both ancestral SARS-CoV-2 strain and pseudotyped viruses harboring SARS-CoV-2 wildtype, key mutations or variants at the nanomolar level. Furthermore, VHH60 suppressed SARS-CoV-2 infection and propagation 50-fold better and protected mice from death for twice as long as the control group after SARS-CoV-2 nasal infections in vivo. Therefore, VHH60 is not only a powerful nanobody with a promising profile for disease control but also provides evidence for a highly effective and rapid approach to generating therapeutic nanobodies.

Assuntos

Enzima de Conversão de Angiotensina 2 , Anticorpos Neutralizantes , COVID-19 , SARS-CoV-2 , Anticorpos de Domínio Único , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/imunologia , SARS-CoV-2/efeitos dos fármacos , Anticorpos de Domínio Único/farmacologia , Anticorpos de Domínio Único/imunologia , Humanos , Animais , COVID-19/imunologia , COVID-19/virologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/química , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Neutralizantes/farmacologia , Tratamento Farmacológico da COVID-19 , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Células HEK293 , Camundongos Endogâmicos BALB C , Ligação Proteica , Feminino

RESUMO

Objective: We aimed to analyze the factors related to delay in transfer of patients in the post-anesthesia care unit (PACU) and to develop and validate a prediction model for understanding these factors to guide precise clinical intervention. Methods: We collected data from two cohorts of 1153 and 297 patients who underwent surgery and were treated in the PACU at two time points. We examined their clinical features and anesthesia care data using analytical methods such as logistic regression, Random Forest, and eXtreme Gradient Boosting (Xgboost) to screen out variables and establish a prediction model. We then validated and simplified the model and plotted a nomogram. Using LASSO regression, we reduced the dimensionality of the data. We developed multiple models and plotted receiver operating characteristic (ROC) and calibration curves. We then constructed a simplified model by pooling the identified variables, which included hemoglobin (HB), alanine transaminase (ALT), glucose levels, duration of anesthesia, and the minimum bispectral index value (BIS_min). Results: The model had good prediction performance parameters in the training and validation sets, with an AUC of 0.909 (0.887-0.932) in the training set and 0.939 (0.919-0.959) in the validation set. When we compared model 6 with other models, the net reclassification index (NRI) and the integrated discriminant improvement (IDI) index indicated that it did not differ significantly from the other models. We developed a scoring system, and it showed good prediction performance when verified with the training and validation sets as well as external data. Additionally, both the decision curve analysis (DCA) and clinical impact curve (CIC) demonstrated the potential clinical efficacy of the model in guiding patient interventions. Conclusion: Predicting transfer delays in the post-anesthesia care unit using predictive models is feasible; however, this merits further exploration.

RESUMO

Patients with non-small cell lung cancer (NSCLC) and anaplastic lymphoma kinase (ALK) mutations have previously derived substantial benefits from ALK tyrosine kinase inhibitors (ALK-TKIs). However, resistance may develop in some patients. We present a case of co-mutation with anaplastic lymphoma kinase (ALK) and rearranged during transfection (RET)-rearranged NSCLC, representing a novel resistance mechanism to ALK-TKIs, in which the patient exhibited a favorable response to combination therapy with ensartinib and pralsetinib. Notably, the patient survived 12 months without experiencing adverse events, a rare occurrence in ALK-rearranged lung adenocarcinoma cases. This case provides further evidence for the existence of RET rearrangements in ALK-positive lung cancer and their potential treatment response to a combination of ALK inhibitors and pralsetinib. This case underscores that a dual-target therapy involving ALK inhibitors, specifically ensartinib and pralsetinib, could be a viable approach in cases of RET-rearranged lung cancer with concurrent targetable ALK mutations. We propose the consideration of this dual-target approach, specifically employing ensartinib and pralsetinib, in managing RET-rearranged lung cancer coexisting with targetable ALK mutations. Given the potential efficacy of these treatments, it is imperative to proactively conduct molecular profiling tests in NSCLC patients upon the emergence of resistance.

RESUMO

BACKGROUND: Circular RNAs (circRNAs) are involved in the progression of colon cancer (CC). This study aimed to examine the role of a new circRNA circ_0101050 in CC. METHODS: Dual-luciferase reporter and RNA immunoprecipitation analyses were performed to validate the target relationships among maternal embryonic leucine zipper kinase (MELK), microRNA (miR)-140-3 p, and circ_0101050. Expression levels were calculated using western blotting and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Western blotting was performed to evaluate the relative expression of Bcl-2 and Bax proteins to determine cell death. Cell Counting Kit-8 (CCK-8) and colony formation assays were performed to determine the proliferative potential of CC cells. The migration rate of CC cells was evaluated using wound healing assays. Tumor formation tests were performed to determine the effect of circ_0101050 on tumor development in vivo. RESULTS: Elevated levels of circ_0101050 and MELK were observed in CC. By inhibiting circ 0,101,050 or MELK, CC cell proliferation and migration were inhibited, but CC cell apoptosis was promoted. Silencing circ_0101050 also inhibited CC growth in vivo. We also found that miR-140-3 p was downregulated, which alleviated the repressive effects of circ_0101050 knockdown on proliferating and migrating CC cells, as well as the stimulating effect on apoptosis. In addition, the absence of MELK alleviated the effects of miR-140-3 p downregulation, which enhanced CC cell malignancy. CONCLUSIONS: Circ_0101050 exacerbates malignant phenotypes in CC by targeting the miR-140-3 p/MELK axis. These findings suggested that the circ_0101050/miR-140-3 p/MELK network may be a prospective target for CC treatment.

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Prinsepia utilis Royle, native to the Himalayan region, has a long history of use in traditional medicine for its heat-clearing, detoxification, anti-inflammatory, and analgesic properties. Oils extracted from P. utilis seeds are also used in cooking and cosmetics. With the increasing market demand, this extraction process generates substantial industrial biowastes. Recent studies have found many health benefits with using aqueous extracts of these biowastes, which are also rich in polysaccharides. However, there is limited research related to the reparative effects of the water extracts of P. utilis oil cakes (WEPUOC) on disruptions of the skin barrier function. AIM OF THE STUDY: This study aimed to evaluate the reparative efficacy of WEPUOC in both acute and chronic epidermal permeability barrier disruptions. Furthermore, the study sought to explore the underlying mechanisms involved in repairing the epidermal permeability barrier. MATERIALS AND METHODS: Mouse models with induced epidermal disruptions, employing tape-stripping (TS) and acetone wiping (AC) methods, were used. The subsequent application of WEPUOC (100 mg/mL) was evaluated through various assessments, with a focus on the upregulation of mRNA and protein expression of Corneocyte Envelope (CE) related proteins, lipid synthase-associated proteins, and tight junction proteins. RESULTS: The polysaccharide was the major phytochemicals of WEPUOC and its content was determined as 32.2% by the anthranone-sulfuric acid colorimetric method. WEPUOC significantly reduced transepidermal water loss (TEWL) and improved the damaged epidermal barrier in the model group. Mechanistically, these effects were associated with heightened expression levels of key proteins such as FLG (filaggrin), INV (involucrin), LOR (loricrin), SPT, FASN, HMGCR, Claudins-1, Claudins-5, and ZO-1. CONCLUSIONS: WEPUOC, obtained from the oil cakes of P. utilis, is rich in polysaccharides and exhibits pronounced efficacy in repairing disrupted epidermal barriers through increased expression of critical proteins involved in barrier integrity. Our findings underscore the potential of P. utilis wastes in developing natural cosmetic prototypes for the treatment of diseases characterized by damaged skin barriers, including atopic dermatitis and psoriasis.

Assuntos

Epiderme , Ácido Graxo Sintases , Extratos Vegetais , Proteínas de Junções Íntimas , Regulação para Cima , Animais , Masculino , Camundongos , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Ácido Graxo Sintases/metabolismo , Ácido Graxo Sintases/genética , Permeabilidade/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Óleos de Plantas/farmacologia , Óleos de Plantas/química , Proteínas de Junções Íntimas/metabolismo , Regulação para Cima/efeitos dos fármacos , Água/química

RESUMO

Cordyceps militaris is a significant edible fungus that produces a variety of bioactive compounds. We have previously established a uridine/uracil auxotrophic mutant and a corresponding Agrobacterium tumefaciens-mediated transformation (ATMT) system for genetic characterization in C. militaris using pyrG as a screening marker. In this study, we constructed an ATMT system based on a dual pyrG and hisB auxotrophic mutant of C. militaris. Using the uridine/uracil auxotrophic mutant as the background and pyrG as a selection marker, the hisB gene encoding imidazole glycerophosphate dehydratase, required for histidine biosynthesis, was knocked out by homologous recombination to construct a histidine auxotrophic C. militaris mutant. Then, pyrG in the histidine auxotrophic mutant was deleted to construct a ΔpyrG ΔhisB dual auxotrophic mutant. Further, we established an ATMT transformation system based on the dual auxotrophic C. militaris by using GFP and DsRed as reporter genes. Finally, to demonstrate the application of this dual transformation system for studies of gene function, knock out and complementation of the photoreceptor gene CmWC-1 in the dual auxotrophic C. militaris were performed. The newly constructed ATMT system with histidine and uridine/uracil auxotrophic markers provides a promising tool for genetic modifications in the medicinal fungus C. militaris.

Assuntos

Agrobacterium tumefaciens , Cordyceps , Transformação Genética , Uracila , Agrobacterium tumefaciens/genética , Agrobacterium tumefaciens/metabolismo , Cordyceps/genética , Cordyceps/metabolismo , Cordyceps/crescimento & desenvolvimento , Uracila/metabolismo , Histidina/metabolismo , Uridina/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Técnicas de Inativação de Genes , Hidroliases/genética , Hidroliases/metabolismo , Genes Reporter , Mutação , Recombinação Homóloga

RESUMO

Most of vaccinees and COVID-19 convalescents can build effective anti-SARS-CoV-2 humoral immunity, which helps preventing infection and alleviating symptoms. However, breakthrough viral infections caused by emerging SARS-CoV-2 variants, especially Omicron subvariants, still pose a serious threat to global health. By monitoring the viral infections and the sera neutralization ability of a long-tracked cohort, we found out that the immune evasion of emerging Omicron subvariants and the decreasing neutralization led to the mini-wave of SARS-CoV-2 breakthrough infections. Meanwhile, no significant difference had been found in the infectivity of tested SARS-CoV-2 variants, even though the affinity between human angiotensin-converting enzyme 2 (hACE2) and receptor-binding domain (RBDs) of tested variants showed an increasing trend. Notably, the immune imprinting of inactivated COVID-19 vaccine can be relieved by infections of BA.5.2 and XBB.1.5 variants sequentially. Our data reveal the rising reinfection risk of immune evasion variants like Omicron JN.1 in China, suggesting the importance of booster with updated vaccines.

Assuntos

Vacinas contra COVID-19 , COVID-19 , Humanos , COVID-19/prevenção & controle , SARS-CoV-2/genética , Infecções Irruptivas , Estudos de Coortes , Evasão da Resposta Imune , Anticorpos Neutralizantes , Anticorpos Antivirais

RESUMO

B-cell lymphoma-2-associated transcription factor 1 (BCLAF1) is a versatile protein involved in the regulation of gene transcription and post-transcriptional processing. Although BCLAF1 exerts a broad tumor suppressor effect or tumor promoter effect in many cancer types, the specific roles concerning its expression levels, and its impact on tumorigenesis in Renal cell carcinoma (RCC) remain unclear. Here, we utilized the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) datasets alongside R software and online tools to unravel the specific roles of BCLAF1 in 33 cancer types, including its expression levels, tumor immune and molecular subtypes, and its correlation with prognosis, diagnosis, DNA methylation, and immune microenvironment. Additionally, we carried out cell biology experiments to independently investigate the expression of BCLAF1 in RCC and its effects on tumor progression. BCLAF1 was differentially expressed in tumor tissues compared to normal tissues across various cancer types and was also differentially expressed in different immune and molecular subtypes. In RCC, patients with high BCLAF1 expression had a better prognosis and BCLAF1 was tightly correlated with the stage, gender, and histological grade of patients. Furthermore, BCLAF1 had higher DNA methylation levels and higher immune infiltration levels in tumor tissues. Additionally, cell functional experiments confirmed the low expression of BCLAF1 in RCC and that BCLAF1 significantly inhibited the proliferation, migration, and invasion, while inducing apoptosis and cell cycle arrest in RCC cells in vitro. Our study under-scored the potential of BCLAF1 as an important actor in tumorigenesis, especially concerning RCC where it may serve as an effective prognostic marker.